chrX-14690691-GTC-G

Variant names:

• chrX-14690691-GTC-G
• rs752610633
• NM_002063.4:c.931-4_931-3delTC

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP6_Moderate BS2_Supporting

The NM_002063.4(GLRA2):​c.931-4_931-3delTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00868 in 833,596 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.010 (0 hom. 2 hem.)
• Consequence: GLRA2 NM_002063.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.180
• Publications: 0 publications found

Genes affected

GLRA2 (HGNC:4327): (glycine receptor alpha 2) The glycine receptor consists of two subunits, alpha and beta, and acts as a pentamer. The protein encoded by this gene is an alpha subunit and can bind strychnine. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

FANCB (HGNC:3583): (FA complementation group B) This gene encodes a member of the Fanconi anemia complementation group B. This protein is assembled into a nucleoprotein complex that is involved in the repair of DNA lesions. Mutations in this gene can cause chromosome instability and VACTERL syndrome with hydrocephalus. [provided by RefSeq, Apr 2016]

FANCB Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group B

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• VACTERL association, X-linked, with or without hydrocephalus

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• VACTERL with hydrocephalus

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP6: Variant X-14690691-GTC-G is Benign according to our data. Variant chrX-14690691-GTC-G is described in ClinVar as Benign. ClinVar VariationId is 2232252.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002063.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA2	NM_002063.4	MANE Select	c.931-4_931-3delTC		splice_region intron	N/A	NP_002054.1	P23416-1
	GLRA2	NM_001118885.2		c.931-4_931-3delTC		splice_region intron	N/A	NP_001112357.1	P23416-1
	GLRA2	NM_001118886.2		c.931-4_931-3delTC		splice_region intron	N/A	NP_001112358.1	P23416-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA2	ENST00000218075.9	TSL:1 MANE Select	c.931-4_931-3delTC		splice_region intron	N/A	ENSP00000218075.4	P23416-1
	GLRA2	ENST00000355020.9	TSL:1	c.931-4_931-3delTC		splice_region intron	N/A	ENSP00000347123.4	P23416-2
	FANCB	ENST00000696351.1		n.*929_*930delGA		non_coding_transcript_exon	Exon 15 of 15	ENSP00000512572.1	A0A8Q3SJA8

Frequencies

GnomAD3 genomes AF: 0.0000917 AC: 10 AN: 109014 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000671

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000588

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000191

Gnomad OTH AF: 0.000692

GnomAD2 exomes AF: 0.00321 AC: 399 AN: 124260 AF XY: 0.0000770

Gnomad AFR exome AF: 0.000657

Gnomad AMR exome AF: 0.00438

Gnomad ASJ exome AF: 0.00642

Gnomad EAS exome AF: 0.00215

Gnomad FIN exome AF: 0.00416

Gnomad NFE exome AF: 0.00320

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00997 AC: 7223 AN: 724539 Hom.: 0 AF XY: 0.00000983 AC XY: 2 AN XY: 203377

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00432 AC: 81 AN: 18744

American (AMR) AF: 0.00313 AC: 80 AN: 25529

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 90 AN: 13000

East Asian (EAS) AF: 0.00268 AC: 60 AN: 22394

South Asian (SAS) AF: 0.00510 AC: 182 AN: 35715

European-Finnish (FIN) AF: 0.00365 AC: 113 AN: 30973

Middle Eastern (MID) AF: 0.00522 AC: 15 AN: 2875

European-Non Finnish (NFE) AF: 0.0117 AC: 6356 AN: 544394

Other (OTH) AF: 0.00796 AC: 246 AN: 30915

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000101 AC: 11 AN: 109057 Hom.: 0 Cov.: 22 AF XY: 0.0000628 AC XY: 2 AN XY: 31857

African (AFR) AF: 0.000100 AC: 3 AN: 29860

American (AMR) AF: 0.000588 AC: 6 AN: 10211

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2597

East Asian (EAS) AF: 0.00 AC: 0 AN: 3498

South Asian (SAS) AF: 0.00 AC: 0 AN: 2550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5621

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 213

European-Non Finnish (NFE) AF: 0.0000191 AC: 1 AN: 52370

Other (OTH) AF: 0.000683 AC: 1 AN: 1465

Alfa AF: 0.0453 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs752610633; hg19: chrX-14708813; COSMIC: COSV107258930;